The major focus of research in gastric physiology over the past several decades has been on the mechanisms that stimulate acid secretion. Much less attention has been paid to machanisms that inhibit acid secretion. Over the past 10 years, we have been engaged in the study of inhibitory mechanisms of the proximal stomach and have accumulated a body of evidence that suggests that an inhibitor of acid secretion and of gastrin release is present in the oxyntic mucosa of the dog. In the past year, we have accomplished preliminary isolation of the inhibitor, first from canine and subsequently from procine oxyntic mucosa. The inhibitor, appears to be a zwitterionic molecule and is probably a small peptide. The present has six specific aims: 1) Definition of the mechanism and site(s) of action of the inhibitory extract using (a) intact animals, (b) isolated perfused stomach preparation, (c) isolated rabbit glands, and (d) isolated parietal cells; 2) Purification and determination of the chemical structure of the inhibitor; 3) Determination of the spectrum of other biological activities and the relative potency for each action; 4) Development of a radioimmunoassay for the inhibitor so as to study its mechanisms of release, pharmacokinetics, cellular origin and physiological significance; 5) Determination of whether vagal inhibition of gastrin release is mediated through the release of the fundic inhibitor; and 6) Search for any potential role of the inhibitor in hypersecretory and hyposecretory gastric disease in man. The isolation of the fundic inhibitor should provide further insight into the physiological mechanisms that control acid secretion and gastrin release. The inhibitor may also be involved in the pathogenesis and pathophysiology of such human diseases as peptic ulcer, hypergastrinemic states, and atrophic gastritis.